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1.
Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics?
Munawar, N, Ahsan, K, Muhammad, K, Ahmad, A, Anwar, MA, Shah, I, Al Ameri, AK, Al Mughairbi, F
International journal of molecular sciences. 2021;(14)
Abstract
Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.
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2.
Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.
Chen, L, He, Y, Wang, X, Ge, J, Li, H
Clinical and translational medicine. 2021;(10):e530
Abstract
Cardiac voltage-gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC-related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life-threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart-related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well-studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.
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3.
Pharmacological Management of Glucose Dysregulation in Patients Treated with Second-Generation Antipsychotics.
Cernea, S, Dima, L, Correll, CU, Manu, P
Drugs. 2020;(17):1763-1781
Abstract
Fasting hyperglycemia, impaired glucose tolerance, prediabetes, and diabetes are frequently present in patients treated with second-generation antipsychotics (SGAPs) for schizophrenia, bipolar disorder, and other severe mental illnesses. These drugs are known to produce weight gain, which may lead to insulin resistance, glucose intolerance, and metabolic syndrome, which constitute important risk factors for the emergence of diabetes. The aim of this review was to formulate therapeutic guidelines for the management of diabetes in patients treated with SGAPs, based on the association between SGAP-induced weight gain and glucose dysregulation. A systematic search in PubMed from inception to March 2020 for randomized controlled trials (RCTs) of diabetes or prediabetes in patients treated with SGAPs was performed. PubMed was also searched for the most recent clinical practice guidelines of interventions for co-morbid conditions associated with diabetes mellitus (DM) (arterial hypertension and dyslipidemia), lifestyle interventions and switching from high metabolic liability SGAPs to safer SGAPs. The search identified 14 RCTs in patients treated with SGAPs. Drug therapy using metformin as first-line therapy and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or perhaps sodium-glucose cotransporter-2 (SGLT2) inhibitors as add-on therapy, might be preferred in these patients as well, as they favorably influence glucose metabolism and body mass index, and provide cardio-renal benefits in general to the DM population, although for the SGLT-2 inhibitors there are no RCTs in this specific patient category so far. Metformin is also useful for treatment of prediabetes. Arterial hypertension should be treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and statins should be used for correction of dyslipidemia. The outcome of lifestyle-changing interventions has been disappointing. Switching from clozapine, olanzapine, or quetiapine to lower cardiometabolic-risk SGAPs, like aripiprazole, brexpiprazole, cariprazine, lurasidone, or ziprasidone, has been recommended.
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4.
Genetic variants in dopamine receptors influence on heterodimerization in the context of antipsychotic drug action.
Faron-Górecka, A, Kuśmider, M, Solich, J, Górecki, A, Dziedzicka-Wasylewska, M
Progress in molecular biology and translational science. 2020;:279-296
Abstract
Human dopamine D2 receptor (D2R) gene has polymorphic variants, three of them alter its amino acid sequence: Val96Ala, Pro310Ser and Ser311Cys. Their functional role never became the object of extensive studies, even though there are some evidence that they correlate with schizophrenia. The present work reviews data indicating that these mutations play a role in dimer formation with dopamine D1 receptor (D1R), with the strongest effect observed for Ser311Cys variant. Similarly, the affinity for antipsychotic drugs of this genetic variant depends on whether it is expressed together with D1R or not. Better understanding of altered ability of genetic variants of D2R to form dimers with D1R, as well as of altered affinity for antipsychotic drugs, depending on the absence or presence of the second dopamine receptor is of great importance-since these two receptors are not always co-expressed in the same cell. It may well be that targeting new compounds toward the D1R-D2R dimers, which the most probably form under conditions of excessive dopamine release, will result in antipsychotic drugs devoid of serious side effects.
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5.
Confirmations, advances and recommendations for the daily care of schizophrenia based on the French national FACE-SZ cohort.
Fond, G, Godin, O, Schürhoff, F, Berna, F, André, M, Aouizerate, B, Capdevielle, D, Chereau, I, D' Amato, T, Dubertret, C, et al
Progress in neuro-psychopharmacology & biological psychiatry. 2020;:109927
Abstract
BACKGROUND The National FondaMental Centers of Expertise (FACE) for Schizophrenia (SZ) have been created to shorten the gap between research and clinical practice. OBJECTIVES To synthetize in a review the 10-year findings issued from the FACE-SZ cohort analyses. METHODS More than 1000 patients were evaluated in 10 expert centers since 2010 with a 2-day long comprehensive standardized battery including neuropsychological testes and physical health assessment and followed-up for 3 years. RESULTS 1. The phase 0 cross-sectional analyses have confirmed well-known data: over-prescription of first-generation antipsychotics, antipsychotic polytherapy and long-term benzodiazepine and under-prescription of clozapine, 13% of drug-induced parkinsonism, 18% of akathisia, a mean duration of untreated psychosis of 18 months, one third of poorly-adherent patients, 24% of metabolic syndrome and 52% of current tobacco smokers with poor care for physical illnesses; a yearly mean financial cost of 15,000 euro/patient. 2. FACE-SZ also yielded additional data in insufficiently explored area: a half of major depression issues (among them one third of undiagnosed major depression and 44% of treated patients with unremitted depression), major depression having a strong impact on Quality of Life independently of negative symptoms, 22% of moderated to severe untreated physical pain. 3. FACE-SZ has explored emerging fields of research, including development of 4 stages- model of schizophrenia, chronic low-grade peripheral inflammation, latent Toxoplasma infection, hypovitaminosis D, and a model for relapse prediction at 2 years. DISCUSSION The associated factors and implications for public health programs were discussed. Based on the FACE-SZ findings and literature, the FACE-SZ group has yielded recommendations to improve daily care for schizophrenia and for future research.
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6.
Sudden Cardiac Death in Schizophrenia: A Review.
Vohra, J
Heart, lung & circulation. 2020;(10):1427-1432
Abstract
In patients with schizophrenia, cardiovascular disease accounts for nearly 50% of deaths and decreased life expectancy, and the incidence of sudden cardiac death is about four times higher than in the background population. While the majority of sudden deaths are due to ischaemic heart disease and its recognised risk factors, about 10% of sudden deaths are unexplained and are thought to be due to cardiac arrhythmias. This review discusses various factors that might contribute to this increased mortality, such as the effect of antipsychotic drugs on potassium and sodium channel function, increased incidence of Brugada pattern in patients with schizophrenia and the role of the autonomic nervous system. It stresses the control of traditional coronary risk factors and discusses various noninvasive tests to identify patients at risk. It also mentions the reported association for nonsynonymous genetic polymorphism rs10503929 within the neuregulin 1 gene (NRG1) and the minor allele C and its role in the risk of sudden cardiac death in schizophrenia.
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7.
Iatrogenic Obesity.
Kumar, RB, Aronne, LJ
Endocrinology and metabolism clinics of North America. 2020;(2):265-273
Abstract
Obesity has been identified as a multifactorial disease with several determinants, including genetic predisposition, environmental influences, dietary patterns, and physical activity factors. Iatrogenic obesity, most commonly medication-induced weight gain, is often overlooked as a contributing factor to a patient's obesity. This article highlights medications known to cause weight gain.
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8.
Association between Serum Lipids and Antipsychotic Response in Schizophrenia.
Kim, DD, Barr, AM, Fredrikson, DH, Honer, WG, Procyshyn, RM
Current neuropharmacology. 2019;(9):852-860
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Abstract
Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled trials, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms.
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9.
Nutrients in Alzheimer's Disease: The Interaction of Diet, Drugs and Disease.
Liyanage, SI, Vilekar, P, Weaver, DF
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 2019;(1):23-34
Abstract
In recent decades, clinical trials in Alzheimer's disease (AD) have failed at an unprecedented rate. The etiology of AD has since come under renewed scrutiny, both to elucidate the underlying pathologies and to identify novel therapeutic strategies. Here, diet has emerged as a potential causative/protective agent. A variety of nutrients, including lipids, minerals, vitamins, antioxidants and sugars as well as broader dietary patterns and microbiotal interactions have demonstrated associations with AD. Although clinical trials have yet to definitively implicate any singular dietary element as therapeutic or causative, it is apparent that dietary preferences, likely in complex synergies, may influence the risk, onset and course of AD. This review catalogs the impact of major dietary elements on AD. It further examines an unexplored reciprocal association where AD may modulate diet, as well as how potential therapeutics may complicate these interactions. In doing so, we observe diet may have profound effects on the outcome of a clinical trial, either as a confounder of a drug/disease interaction or as a generally disruptive covariate. We therefore conclude that future clinical trials in AD should endeavor to control for diet, either in study design or subsequent analyses.
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10.
Neuroleptic malignant syndrome in pregnancy: case report and literature review.
Escobar-Vidarte, MF, Loaiza-Osorio, S, Messa, AA, Macías, GE
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2019;(14):2438-2441
Abstract
BACKGROUND Neuroleptic malignant syndrome (NMS) is a serious complication associated with the use of drugs that affect dopaminergic system neurotransmission. The occurrence of NMS during pregnancy or gestation is considered a life-threatening obstetric emergency. CASE We are reporting the first case in Latin America of NMS in one pregnant women with acute psychotic episode. One day after starting with antipsychotic therapy, she developed a fever higher than 39.0 °C with tachycardia, tachypnea, generalized muscle rigidity and somnolence, with creatine kinase (CPK) levels evidencing a result of 2800 U/L. She was treated successfully with levetiracetam, biperiden and quetiapine. DISCUSSION A search in PubMed, Embase and Ovid from 1988 to 2016 resulted in seven cases reported in either pregnant or puerperal women. In general, NMS resolves within 3-14 days; most NMS cases reported during pregnancy have involved the use of haloperidol (5 case reports) which is concordant with this report. The obstetric results were good in cases reported, only two women showed signs, among them: hyperemesis gravidarum and preterm delivery. Most of the pregnant women who had NMS presented other associated comorbidities, being mostly of infectious origin. In other investigations, it has been affirmed that NMS can become lethal in adults; however, in our search for pregnant women with this disease, no associated mortality was found. CONCLUSIONS NMS is seen infrequently during pregnancy. The clinical diagnosis requires high suspicion by the examiner. It is important that obstetricians timely recognize the condition.